The role of hepatocyte growth factor and β1-integrin/cell-matrix interactions in regulating growth and tunneling nanotube formation in non-small cell lung cancer

Awanis, Griselda (2022) The role of hepatocyte growth factor and β1-integrin/cell-matrix interactions in regulating growth and tunneling nanotube formation in non-small cell lung cancer. Doctoral thesis, University of East Anglia.

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Non-small cell lung cancer (NSCLC) accounts for 85% of all lung cancer cases. It is associated with high mortality rates with the majority of patients diagnosed with advanced metastatic cancer. Evading programmed cell death, increasing cellular motility, suppressing immune reactivity and alterations in the interactions between tumour cells and the extracellular matrix (ECM) proteins outline the complex process of tumour invasion. Another vital understudied aspect in achieving metastasis is the cellular communication existing between cells through the formation of tunneling nanotubes (TNTs). TNTs are non-adherent F-actin-based cytoplasmic protrusions that transport organelles to propagate chemoresistance across long distances in the tumour microenvironment (TME). Moreover, different factors within the TME initiate the pro-tumourigenic processes. Hepatocyte growth factor (HGF) and its receptor, c-Met, are mutationally upregulated in NSCLC leading to aberrant signalling in NSCLC which contributes to enhanced proliferation, migration and invasion. Similarly, other pleiotropic cytokines, such as IL-6 and EGF, are also known to induce growth and invasion in NSCLC. Furthermore, remodelling of the ECM proteins such as collagen IV, fibronectin and laminin results in the propagation of growth factor signalling via β1-integrin (Yan et al. 2006). Therefore, the aim of this research was to investigate the crosstalk between HGF with other pleiotropic cytokines (e.g. IL-6 and EGF) and the ECM/β1-integrin signalling axis in inducing proliferation and TNT formation in A549 lung adenocarcinoma cells.

The results of this thesis demonstrate a novel role for the combined HGF and IL-6-induced proliferation via a convergence on the MAPK pathway. Moreover, HGF mediated proliferation in A549 cells occurred via interactions with fibronectin and β1-integrin. Our results also presented a novel role for HGF and its signalling axis in TNT formation, whereby HGF/c-Met crosstalk with β1-integrin to activate Arp2/3 complex, MAPK and PI3K pathways via paxillin. C-Met, β1-integrin and paxillin were also identified as novel components of TNTs. HGF/c-Met also crosstalk with EGF/EGFR via a convergence on the MAPK and PI3K pathways to regulate TNT formation. Moreover, we discovered a subpopulation of A549 cells capable of simultaneous migration, TNT formation and cell division which highlights a novel potential mechanism of metastasis in NSCLC. To recapitulate the 3D TME, our 3D A549 tumouroid studies revealed a physical interaction with occurring between A549 tumouroids and eosinophils. Moreover, novel TNT formation was observed between A549 tumouroids upon triptolide treatment. Overall, our findings highlight the complex interactions within the TME and the importance of multi-drug targeting to fully inhibit the spectrum of protumourigenic effects induced by HGF/c-Met and its signalling partners.

Item Type: Thesis (Doctoral)
Faculty \ School: Faculty of Science > School of Pharmacy
Depositing User: Chris White
Date Deposited: 22 Mar 2023 09:14
Last Modified: 22 Mar 2023 09:14

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